Iopromide, 5-methoxyacetylamino-2,4,6-triiodo-isophthalic acid-[(2,3-dihydroxy-N-methyl-propyl)-(2,3-dihydroxypropyl)]-diamide of Formula (I), is an iodine-containing X-ray contrast agent, and it has 3 bulky iodine atoms on the 2, 4, and 6 positions of the phenyl group, which sterically hinder the free rotation of the dihydroxypropyl-N-methylamino group, so that two atropisomer occur (M. Oki, Topics in Stereochemistry, volume 14, 1983, pp. 1˜81; and H. Staab, et al., Tetrahedron Letters, No. 38, 1966, pp. 4593˜4598).

Besides the two atropisomers of Iopromide, there also exist E and Z isomers produced due to the steric hindrance of the free rotation between the carbon atom and nitrogen atoms of the amide bonds. Accordingly, iopromide is composed of a mixture of four isomers, and E1, E2, Z1 and Z2. In one of the atropisomers, the substituted nitrogen atom lies above the plane of the benzene ring of iopromide, while in the other, it lies below the plane of the benzene ring.
As shown in Formulae 2A and 2B, the E and Z forms can be distinguished by the arrangement of the substituents around C—N bond of the dihydroxy-N-methyl-proyl amide group.

wherein,
R is a phenyl group of iopromide.
These isomers have different physical properties and the relative amount of a singe isomer as well as the relative contents of the isomers is regulated in a pharmaceutical formulation. According to the United States Pharmacopoeia, 31st Edition, 2008, pp 2433-2435, a pharmaceutical raw material must contain 40 to 50% of form 1 isomer and 49 to 60% of form 2 isomer, and a medicinal product must contain 8.0 to 12.0% of E1 isomer, 9.0 to 14.0% E2 isomer, 32.0 to 40.0% of Z1 isomer, and 38.0 to 46.0% of Z2 isomer.
On the other hand, no effective method for crystallizing iopromide is currently available. U.S. Pat. No. 4,364,921 discloses a method for preparing iopromide, but, it does not employ a final crystallization step. Although European Patent EP 1,025,067 and English Patent GB 2,280,436 disclose a method for washing and crystallizing iopamidol and iodixanol, they do not teach any crystallization procedure for iopromide or iopromide isomers.
An injection formulation of iopromide can be prepared by dissolving a pharmaceutical raw material in water, adding pharmaceutically acceptable excipients to the solution, and sterilizing it, but, when a conventional iopromide raw material containing E and Z isomers is used to formulate a pharmaceutical product, the relative contents of the isomers in the product often do not meet the regulation.
International Publication No. WO 2007/065534 discloses a method for recovering iopromide suitable for pharmaceutical purposes from an iopromide solution. However, it merely teaches the isolation of form 1 and 2 isomers, and, therefore, it is difficult to selectively obtain Z isomer of iopromide.
The present inventors have found that a method for selectively resolving and crystallizing Z isomer of iopromide from crystalline iopromide or an iopromide concentrate containing E and Z isomers.